Diagnosing PML Joseph R. Berger, M.D. University of Kentucky For - - PowerPoint PPT Presentation

Diagnosing PML

Joseph R. Berger, M.D. University of Kentucky

For Session 4: Ongoing Research Transatlantic EMEA-FDA PML Workshop

Standard PML Diagnostic Measures

• Clinical Diagnosis
• 1. Clinical manifestations c/w PML
• Examples: Hemiparesis, sensory abnormalities,

hemianopsia, aphasia, dysarthria, behavior changes

• Exclude such findings as optic neuritis and myelitis

PML in AIDS - Clinical Features

(in descending order of frequency)

• Symptoms

– Weakness – Cognitive impairment – Speech abnormalities – Headache – Gait impairment – Visual abnormalities – Sensory loss – Seizures – Limb incoordination

• Signs

– Hemiparesis – Gait disturbance – Cognitive impairment – Dysarthria – Dysphasia – Hemisensory loss – Visual field defect – Ocular palsy

Berger et al, J Neurovirol 1998;4:59-68.

Standard PML Diagnostic Measures

• Clinical Diagnosis
• 1. Clinical manifestations c/w PML
• Examples: Hemiparesis, sensory abnormalities,

hemianopsia, aphasia, dysarthria, behavior changes

• Exclude such findings as optic neuritis and

myelitis

• 2. MRI features c/w PML

Radiographic Characteristics of PML

CT Scan

• hypodense lesions
• rare contrast enhancement

MRI

• increased signal on T2WI and FLAIR
• hypointense on T1WI
• no mass effect (present occasionally with IRIS)
• often parieto-occipital and frontal lobes
• atypical locations

– cerebellum, brainstem, basal ganglia, temporal lobe

• Gd enhancement speckled or thin rim(30-40% of

natalizumab associated PML; <15% of AIDS)

Whiteman M et al: Radiology 1993;187:233-40; Berger JR et al: J Neurovirol 1998;4:59-68.

CT and MRI in PML

Contrast enhancement of MRI

Radiologic-Pathologic Correlation in PML

Standard PML Diagnostic Measures

• Clinical Diagnosis
• 1. Clinical manifestations c/w PML
• Examples: Hemiparesis, sensory abnormalities,

hemianopsia, aphasia, dysarthria, behavior changes

• Exclude such findings as optic neuritis and

myelitis

• 2. MRI features c/w PML
• 3. CSF JCV+ by PCR

PML

CSF Caveats

• False negatives

– Routine PCR – 25% – Ultrasensitive PCR – 5%

• False positives (?)1

– 2/217 (0.9%) MS CSF with JCV+ – 1/210 (0.5%) cell free CSFs– 103 copies/ml – 1/42 (2.4%) CSF cell samples – 25 copies/ml – Low copy numbers

• Persistently positive CSF JCV PCR2

– 13/35 MS patients with natalizumab PML CSF JCV+ after IRIS – Up to 5 months out JCV still detectable

• 1. Iacobaeus E et al: Mult Scler 2009;15:28-35. 2. Ryschkewitsch CF et al: Ann Neurol 2010;68:384-91.

Gold Standard for PML Diagnosis

• Brain pathology at biopsy or autopsy

Characteristic histopathological triad

• 1. Demyelination
• 2. Bizarre astrocytes
• 3. Enlarged oligodendroglial nuclei

Demonstration of the virus by EM or immunohistochemistry

PML

Demyelination in PML

Classic Histopathological Triad of PML

“Puffballs” of demyelination

Axonal preservation Bizarre astrocytes Enlarge oligodendroglial nuclei

Demonstration of JCV in Tissue

Biotinylated stain Fluorescein label

Electron microscopy

Immunohistochemist ry

Radiographically Isolated PML

• 23 year old man with MS on natalizumab for 24 months shows new
• lesion. One month later he is recognized to have inappropriate

behavior on routine visit.

Langer-Gould A et al: N Engl J Med 2005;353:375-81.

October 2003 October 2004

Radiographically Isolated PML

• 35 year old man started on

natalizumab in Jan 2007

• Jan 2008 MRI shows early

lesion (read as no new lesions)

• Developed myoclonic

jerking of left arm in Apr 2008

• MRI abnormality evident

by Jul 2008

Linda H et al: N Engl J Med 2009;361:1081-7

Radiographically Isolated PML

• A high index of suspicion of PML must be

entertained even in the absence of any clinical manifestations

• Diagnostic criteria must be expanded to

permit diagnosis of PML based on radiographic and laboratory criteria (CSF JCV PCR +)

PML Diagnostic Uncertainty

• 27 year old man with MS symptoms

since teens

• MS dx established in 2006
• Apr 2008, natalizumab start
• Allergic reaction with infusions
• Aug 2008, 1 month after 4th infusion,

presents with confusion, behavioral changes and worsening left hemianesthesia and dysarthria

• CSF: 14-28 WBCs; prot 55; IgG

index 2.5; MBP 4.9; JCV PCR negative x 2

• 1 dose of IVMP and PLEX
• Significant recovery and alive at 36

months

• Giant MS plaque or aborted PML

with negative CSF

APR 08 FLAIR AUG 08 FLAIR AUG 08 CE

Twyman and Berger: J Neurol Sci 2010; 15:110-3.

To learn how to treat disease, one must learn how to recognize it. The diagnosis is the best trump in the scheme of treatment.

Jean Martin Charcot 1825-1893